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Biomedical subjects

W Oster

Publications and source records attributed to W Oster.

68 records · Page 4Linked to original sources
PubMed1988

Identification and purification of human erythroid progenitor cells by monoclonal antibody to the transferrin receptor (TU 67).

Anti-TU 67 is a murine monoclonal antibody that recognizes the transferrin receptor. With respect to hematopoietic cells TU 67 is expressed by human multipotent colony-forming cells (CFU-Mix), erythroid progenitor cells (BFU-E and CFU-E) and a fraction of granulocyte/monocyte colony forming cells, but is not expressed by mature hematopoietic cells including erythrocytes, platelets, lymphocytes, and peripheral blood myeloid cells. The TU 67-positive fraction of normal bone marrow, separated by fluorescence-activated cell sorting (FACS) or immune rosettes, contained 87% of the erythroid progenitor cells. Erythroid progenitor cells were enriched up to 50-fold by using a combination of monoclonal antibodies to deplete mature hematopoietic cells, followed by positive selection of BFU-E and CFU-E by TU 67 antibody.

Antibodies, Monoclonal↗
PubMed1988

Incidence of lineage promiscuity in acute myeloblastic leukemia: diagnostic implications of immunoglobulin and T-cell receptor gene rearrangement analysis and immunological phenotyping.

Sixty-nine blood or bone marrow samples from both children and adults with acute myeloblastic leukemia (AML) were investigated to elucidate the frequency of immunoglobulin (IG) and T-cell receptor (TCR)-gene rearrangements. Non-germline configuration for the IG heavy chain (h) gene was detected in the specimens of nine patients of various subtypes according to the French-American-British classification (FAB), including FAB M1, M2, M4 and M5. Rearrangement of the IG kappa chain (k) gene was present in one of these cases which simultaneously revealed a rearranged TCR-beta (b) chain gene. In another two AML samples we found TCR-b gene rearrangements, in one case in combination with an IG-h gene rearrangement. IG-h gene rearrangements were detected in 10 cases, in one case in conjunction with an IG-kappa (k) and TCR-b gene rearrangement. A highly significant correlation between the occurrence of DNA rearrangements of the IG-h locus and nuclear staining with the enzyme terminal deoxynucleotidyl transferase (TdT) and surface expression of the CD 19 and CD 34 antigen could be identified: all 10 TdT positive AML samples rearranged IG-h. Similarly, six out of 69 AML samples exhibited surface expression of CD 19, five of these in combination with CD 34 and all of them rearranged the IG-h gene. The one leukemia with TCR-b gene rearrangement only was TdT positive as well, but did not express CD 19 or CD 34. We conclude that IG-h gene is rearranged in a substantial proportion of AML, strongly associated with a specific immunophenotype (TdT+, CD19+, CD34+), whereas TCR-b gene rearrangement appears more rarely. No positive correlation between occurrence of IG-h and TCR-b gene-rearrangements and one AML FAB-subtype was found, although a clustering of M1 and M4 FAB subtypes in the AML group showing reconstructed IG-h gene became evident.

Adult↗
PubMed1988

Interleukin 1 stimulates T lymphocytes to produce granulocyte-monocyte colony-stimulating factor.

T lymphocytes are thought to cooperatively interact with monocytes to produce colony-stimulating factors (CSF). However, little is known about monocyte-mediated signals leading to CSF-secretion by T lymphocytes, although soluble monocyte products have been implicated. We have employed monoclonal antibody anti-T3B covalently coupled to CnBr-activated Sepharose 4B beads, to show that multimeric ligation of T cell antigen receptor leads to T cell receptiveness to interleukin 1 (IL-1), as indicated by T cell production of CSF, which induces growth of myeloid progenitor cells into neutrophil, eosinophil, and monocyte colonies. To investigate the molecular basis of these findings, total RNA was extracted from T3B Sepharose-primed and IL-1-stimulated T lymphocytes and probed for granulocyte-monocyte-CSF (GM-CSF), granulocyte-CSF (G-CSF), and monocyte-CSF (M-CSF) mRNA. GM-CSF, but not G-CSF or M-CSF, messages were detected. Nuclear "run on" assays revealed that IL-1 action is effective primarily at the level of GM-CSF gene transcription. These results suggest a previously unrecognized role of IL-1 in the regulation of GM-CSF secretion by T cells.

Colony-Stimulating Factors↗
PubMed1988

[Cytokines in tumor therapy].

The use of recombinant cytokines offers a new dimension in cancer treatment. While the effects of cytotoxic chemotherapy are relatively nonspecific and affecting all rapidly proliferating tissues, these hormone-like, physiologically produced substances are able to modulate tumor-host interactions and in addition may interact with pathogenetically relevant disturbances in growth related cellular functions. The latter principle seems to be of major importance for the impressive results of interferon alfa treatment in hairy cell leukemia. The expected anti-tumor effects of tumor necrosis factor alfa and of interleukin-2 activated killer cells, however, have only been observed in occasional patients, most of them with rare tumors. A more immediately promising therapeutic approach seems to be at hand with the hemopoietic growth factors. They are able to stimulate the non-specific system of host defense as well as the hemopoietic progenitor cell compartment, relevant for reconstitution after aplasiogenic chemotherapy and bone marrow transplantation and thus in near future could be of great importance in the treatment of tumor diseases.

Growth Substances↗
PubMed1988

Yeast-expressed granulocyte-macrophage colony-stimulating factor in cancer patients: a phase ib clinical study.

The in vivo effect of yeast-derived recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was investigated in 29 patients with advanced malignancy in phase Ib trial. Patients were treated at six different dose levels (30-1000 micrograms/m2/day) with either daily intravenous bolus injection or 24 hours continuous infusion for 5 days or 2 weeks. Administration of rh GM-CSF resulted in a broad spectrum of dose-, route-, and schedule-dependent hematopoietic effects. Sustained infusion of rh GM-CSF elicited a maximum 17-fold average peak increase of the total white blood cell (WBC) count with mainly neutrophils, eosinophils, and monocytes accounting for this rise, and increases in bone marrow cellularity with a shift to immature myeloid elements. Elevation of lymphocytes, platelets and reticulocytes was not induced. Within one week after discontinuation of treatment the leukocytosis had disappeared. Adverse reactions encountered with rh GM-CSF seen in 65% of the patients studied were never life-threatening and always reversible. They included mild myalgias, facial flushing, low-grade fever, headache, bone discomfort, nausea, dyspnoea and transient decline of platelet counts. These results suggest that rh GM-CSF can be safely administered at the doses and schedules employed and that it can induce in vivo some of the biological effects reported in in vitro studies. Although no objective antitumour responses have been seen, the ability of rh GM-CSF to increase turnover and function of leukocytes in vivo may prevent neutropenia and infections, when GM-CSF is adjunctively added to cytotoxic cancer therapy.

Adult↗
PubMed1988

Regulation of gene expression of M-, G-, GM-, and multi-CSF in normal and malignant hematopoietic cells.

Colony stimulating factors (CSFs) are produced by a variety of cell types, including T-lymphocytes (T cells) and mononuclear phagocytes; both cell types are known to cooperatively interact to elaborate CSFs, although the specific cellular source of CSF species and mechanisms of intercellular communications in this regard are poorly understood. In this report, we investigate the specific origin of various CSF species in peripheral blood mononuclear cells (PBMC), purified T-lymphocyte and monocyte (Mo) populations. Furthermore, we assess the conditions required for stimulation of purified cell cultures to express CSF messenger RNAs (mRNAs) and proteins. In the absence of exogenous activation stimuli, human PBMC, T cells and Mo failed to produce transcripts for CSF for macrophages (M-CSF or CSF-1), for granulocytes (G-CSF), for granulocytes/macrophages (GM-CSF), and for multilineage CSF (multi-CSF or Il-3). However, after stimulation with phorbol myristate acetate (PMA) and phytohemagglutinin (PHA), mRNAs for M-, G-, GM-CSF, and multi-CSF became detectable in PBMC as early as 6 hours after initiation of cultures. Identical culture conditions resulted in synthesis of G-, and M-CSF mRNA by Mo, whereas T-lymphocytes produced GM-CSF and multi-CSF mRNA. More physiologically, when Mo were activated with interferon (IFN)-gamma or tumor necrosis factor-alpha (TNF-alpha) and T-lymphocytes were stimulated in an Mo-independent pathway, that is via triggering of the 50 kd sheep erythrocyte receptor protein employing monoclonal antibodies (mo ab) to the Tll-2- and Tll-3- defined epitopes, similar kinetics of mRNA expression were obtained. Similarly, when interleukin-1 (Il-1) receptive T cells were stimulated with Il-1, T cells transcribed functionally active GM-CSF and multi-CSF. Maximum peak activity of GM-, G-, and M-CSF protein secretion was identical for all CSF species investigated, and occurred in culture 48-72 hours after specific induction. Constitutive expression of CSFs not found in unactivated normal hematopoietic cells was, however, frequently observed in blast cell populations of patients with acute myeloblastic leukemia. Of 49 AML samples, 15 revealed G-CSF transcripts; 11, GM-CSF mRNA; and 6 samples synthesized M-CSF mRNA. Employing specific bioassays, 12 of 15 G-CSF-mRNA-producing cell populations, 8 of 11 GM-CSF-mRNA-producing cell populations, and 1 of 6 M-CSF-mRNA-synthesizing samples, demonstrated release of the respective functionally active CSFs into their culture supernatants.(ABSTRACT TRUNCATED AT 400 WORDS)

Blotting, Northern↗
PubMed1988

Constitutive expression of hematopoietic growth factor genes by acute myeloblastic leukemia cells.

Blast cell populations of forty nine individuals with acute myeloblastic leukemia (AML) were investigated for constitutive expression of genes for various hematopoietic growth factors. Fifteen samples constitutively exhibited messenger (m) RNA for colony stimulating factor for granulocytes (G-CSF). Eleven AML specimens produced mRNA specific for CSF for granulocyte and macrophages (GM-CSF). When probed for CSF for macrophages (M-CSF or CSF-1) specific hybridization signals became detectable in six samples. Five out of six blast cell populations transcribing M-CSF, synthesized G-, and GM-CSF mRNA's simultaneously, whereas another five leukemias transcribed G-, and GM-CSF genes exclusively. Furthermore, when specific bioassays were performed to detect secretion of biologically active CSF proteins by these leukemic blast samples, twelve out of fifteen G-CSF mRNA producing cell populations, eight out of eleven GM-CSF mRNA producing cell populations and one out of six M-CSF mRNA synthesizing samples, demonstrated release of the respective, functionally active CSF's into their culture supernatants. Our results show that gene transcription and protein secretion of hematopoietic growth factors are features that are frequently detected in leukemic myeloid blast cells and involve G-, GM-, and M-CSF. With respect to recent findings of receptiveness of leukemic colony forming cells (L-CFC) for proliferative stimuli provided by various hematopoietic growth factors, our findings point out a potential role of autocrineously produced CSF's in the pathophysiology of autonomous proliferation in AML.

Blotting, Northern↗
PubMed1987

Tumor necrosis factor (TNF)-alpha but not TNF-beta induces secretion of colony stimulating factor for macrophages (CSF-1) by human monocytes.

Tumor necrosis factor (TNF)-alpha has been identified as a major inducer of colony stimulating factor (CSF)-secretion by human vascular endothelial cells and fibroblasts. In the present study we assessed the capacity of TNFs to induce release of CSF-1 from highly purified peripheral blood monocyte preparations. Whereas monocytes do not accumulate CSF-1 messenger (m)RNA constitutively and consequently do not produce CSF-1 protein, CSF-1 mRNA and protein secretion became detectable, when monocytes were cultured in the presence of TNF-alpha, that was synergistically enhanced by interferon-gamma (IFN-gamma). However, under identical experimental conditions TNF-beta failed to induce monocyte CSF-1 synthesis. Cultures of monocytes in the presence of TNF-beta before addition of TNF-alpha abolished the CSF-1 inducing capacity of TNF-alpha, suggesting that TNF-beta may act as antagonist to TNF-alpha for CSF-1 production. These data point out a previously unrecognized function of TNF-alpha to modulate CSF-1 release by monocytes and demonstrate disparate biological properties of different TNF species in hematopoiesis.

Colony-Forming Units Assay↗
PubMedDate not supplied

Control of blast cell proliferation and differentiation in acute myelogenous leukemia by soluble polypeptide growth factors.

Proliferation of acute myelogenous leukemia (AML) derived blast cells requires the presence in culture of one or more growth factors. In the majority of cases Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate clonogenicity of AML blasts, which can be synergised by Interleukin-6 (IL-6), Interleukin-1 (IL-1) and granulocyte colony-stimulating factor (G-CSF). In contrast, macrophage colony-stimulating factor (M-CSF) favors deterministic divisions. A substantial part of AML samples have clonogenic cells which, however, proliferate autonomously in vitro. The production by leukemic cells of a variety of growth or synergizing factors including GM-CSF, G-CSF, IL-1, IL-6, and Tumor Necrosis Factor (TNF) has been demonstrated and a fraction of cases will use these molecules to support clonogenic growth in an autocrine or paracrine fashion. However, unlike the situation with retrovirus-induced murine or avian leukemias, the role of production of CSFs and other cytokines by human leukemic cells in the transformational process remains uncertain.

Biological Factors↗
PubMedDate not supplied

Monokines: stimulatory and inhibitory regulator molecules of myelopoiesis in vitro.

The conditions for monocytes to secrete molecules that are involved in myelopoiesis, i.e. Colony Stimulating Factors (CSFs), Interleukin-1 (IL-1) and Tumor Necrosis Factor-alpha (TNF-alpha) were investigated. Whereas secretion of these molecules by monocytes is negligible in a quiescent state, activation of monocytes with Interferon-gamma (IFN-gamma) results in mRNA accumulation and subsequent protein secretion of CSF for granulocytes (G-CSF) and for monocytes (M-CSF). Under identical conditions mRNA-transcripts of TNF-alpha, IL-1-alpha and IL-1-beta genes were induced. Whereas IFN-gamma induces secretion of TNF-alpha protein, protein secretion of IL-1 by monocytes failed to occur in response to an IFN-gamma stimulus. However, the presence in culture of IFN-gamma in combination with TNF-alpha induced secretion of IL-1. Although IL-1 regulates the production of CSF for granulocytes and monocytes (GM-CSF) by IL-1 receptive T-lymphocytes, and is therefore involved in upregulatory mechanisms of myeloid growth, it may be able to suppress growth of myelopoietic progenitor cells (MPC) as well, when hematopoietic cultures are depleted of cells, that have the potential to secrete CSFs. Similarly, IFN-gamma, although being a major inducer of CSF secretion by monocytes, was shown to inhibit myeloid colony growth when exposed to purified MPC and allowed to synergize with TNF-alpha.

Biological Factors↗